Growing an artificial lung

Dr. Thomas Petersen, Yale University

Chris - Also in the news this week, researchers at Yale University in America have come one step closer to building a functional lung in the laboratory. The team stripped cells off the lung of a rat which left behind a connective tissue scaffolding which they then repopulated with new cells, and this newly formed lung successfully exchanged oxygen and carbon dioxide for a short time after it was transplanted into another recipient rat. And this offers hope that we might be able to build replacement lung tissue for people in the future. Well joining us to tell us a bit more about how he made this happen is one of the researchers, Dr. Thomas Petersen who is a Post Doctoral Associate in Biomedical Engineering at Yale.

Hello, Thomas. Thank you for joining us on the Naked Scientists. Tell us first of all Ė I gave a very brief summary and overview there Ė how did you actually do this work?

Thomas - Well you gave a very excellent summary. We start with a normal lung of a rat and treat it with a chemical solution to remove all the cells and this gives us this three-dimensional scaffold or skeleton of a lung, and thatís a very important part because the 3D structure of a lung is quite complex and something that we couldnít easily make in the laboratory if we wanted to. So we can't make an artificial material that is in a shape of a lung. This scaffold can then be seeded with cells. A variety of cell types we used Ė both blood vessels cells and airway cells, and then we cultured this growing tissue in the lab for about a week, after which we can take it out and study it in a variety of ways, and we can also transplant it into rats as you mentioned.

Chris - And once you've got the scaffolding, how did the cells that you transplant onto that scaffolding know where to go, and what sorts of cells to turn into?

Thomas - Thatís a very good question. So there are two things that we did to try and help the cells go to the right places. The first - at a very high level - is we put them into the right compartments. So in the lung, you pretty much have two areas. You have the airway compartment and the blood vessel compartment, and so at a very high level, we just put the blood vessel cells into the blood vessels and the airway cells into the airways. The second thing we did to try and help this was during this one week of growth in the lab, we provided stimuli to the lung, so the lung was being breathed, similar to the way a patient is breathed on a ventilator, and we also pumped nutrients; a nutrient solution, through the blood vessels of the lung. So these two stimuli helped to encourage the cells to grow in more normal lung patterns. But certainly, we don't fully know why all of the cells seem to go to the right places, and thatís something that weíre interested in trying to look into further, going forward.

Chris - Because one of the interesting things about lungs is that itís not just a bunch of blood vessels and a bunch of airway cells. There are individual different types of cells in both structures but certainly in the airways, there are things like cells that make the surfactant, the chemical that makes the water lose its surface tension so the airways don't collapse for example. Those cells appeared and populated the airways in the right numbers in your tests. Do you think there are signals coming off of that underlying scaffold that direct the cells to turn into certain specialised forms?

Thomas - Yes, absolutely. Our most likely scenario is that there are cues left behind on this empty three-dimensional scaffold that are helping to direct the right cells to adhere to the right spots on the lung. There are other possibilities that weíre interested in looking into, but thatís really the most likely scenario, that there are some cellular signals that are staying behind on the scaffold.

Chris - And you were able to take this regrown lung which took what Ė a week or so to regrow? And then put that into a recipient animal.

Thomas - Thatís correct. So we performed left lung transplants on several animals. This is only short-term transplants for up to 2 hours, but they did work quite well. There were no large leaks of air or blood, and the primary function weíre looking at evaluating is, as you said earlier, gas exchange. So whether the lungs can oxygenate the blood thatís flowing through them and whether they can remove carbon dioxide out of the blood, and they performed very well on both of those aspects.

Chris - Why did you only go for 2 hours? Was that all that you had permission to do, or was it that the lungs at some point failed beyond that point, and thereís more work to do?

Thomas - Right. Well itís a combination of both of those. We do have limitations on what we can do in the animals and 2 hours was our objective and the lungs were still doing fine. They were still breathing, there were still blood flowing through them after 2 hours, but certainly, we wouldnít right now expect that they would have functioned as well for a day or maybe even several hours. After 2 hours in some of the lungs, we were able to see small blood clots forming in some areas, and certainly, that wouldíve gotten worse over time, and thatís one of the things we need to work on in this going forward is, ensuring that no blood clots form in the engineered lung.

Chris - Now one obvious direct application of this is to say, well, if we do lung transplants on humans, whilst this does save lives, the long term prognosis is still quite poor because the immune system moves in and causes damage, infections move in and cause damage, and therefore, itís not a perfect solution. If we could take a lung scaffold and populate it with the personís own cells, so we didnít have to reduce the activity of the immune system, this would presumably be a very big short term goal for work of this type.

Thomas - Right. I would still call that a long term goal. We do obviously want to transition this work into human tissue, and the way to do that would be to start with a human or similarly sized lung scaffold and then obtain cells from a given patient. And they are having advances lately involving stem cell work, involving adult-derived stem cells that we could possibly use to repopulate this human lung scaffold, and that would avoid rejection in a transplant patient. I would estimate it would still take say, 20 years before we can grow a fully functional human lung in the laboratory.

Chris - Although I guess the ultimate goal and the reason I said a shorter term goal versus a longer term one is that you really want to be able to produce a complete lung de novo by using say, microfabrication techniques or something to lay down a scaffold so you don't have to borrow someone elseís.

Thomas - Yes. Well thereís a few ways in which you could get the scaffold to begin with. The first option would be a human lung that is not suitable for transplant, and there are quite a few available lungs that are just simply not good enough to use for transplant. Itís also possible to potentially use the lung of a primate or even a pig. The molecules that make up this lung scaffold are highly conserved or highly similar across these species, and it would be highly unlikely that they would be recognised by the body as foreign Ė meaning they would not then be rejected.

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